pantetheine and Cystinosis

Pantethine, the stable disulfide form of pantetheine, is the major precursor of coenzyme A, which plays a central role in the metabolism of lipids and carbohydrates. Coenzyme A is a cofactor in over 70 enzymatic pathways, including fatty acid oxidation, carbohydrate metabolism, pyruvate degradation, amino acid catabolism, haem synthesis, acetylcholine synthesis, phase II detoxification, acetylation, etc. Pantethine has beneficial effects in vascular disease, it able to decrease the hyperlipidaemia, moderate the platelet function and prevent the lipid-peroxidation. Moreover its neuro-endocrinological regulating role, its good influence on cataract and cystinosis are also proved. This molecule is a well-tolerated therapeutic agent; the frequency of its side-effect is very low and mild. Based on these preclinical and clinical data, it could be recommended using this compound as adjuvant therapy.

Topics: Acetylcholine; Animals; Antioxidants; Atherosclerosis; Blood Platelets; Cataract; Central Nervous System; Coenzyme A; Cystine; Cystinosis; Dietary Carbohydrates; Fatty Acids; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipid Peroxidation; Oxidation-Reduction; Pantetheine; Pantothenic Acid; Pyruvates

D-Pantethine is a conjugate of the vitamin pantothenic acid and the low-molecular-weight aminothiol cysteamine. Pantethine is an experimental hypolipemic agent and has been suggested as a source of cysteamine in the treatment of nephropathic cystinosis. We treated four cystinotic children with 70-1,000 mg/kg per d oral D-pantethine and studied its metabolism. Pantethine was rapidly hydrolyzed to pantothenic acid and cysteamine; we could not detect pantethine in plasma after oral administration. The responsible enzyme, "pantetheinase," was highly active in homogenates of small intestinal mucosa and plasma. The Michaelis constant of the rat intestinal enzyme was 4.6 microM and its pH profile showed a broad plateau between 4 and 9. Pantothenate pharmacokinetics after orally administered pantethine followed an open two-compartment model with slow vitamin elimination (t1/2 = 28 h). Peak plasma pantothenate occurred at 2.5 h and levels over 250 microM were seen at 300 times normal. Apparent total body storage of pantothenate was significant (25 mg/kg), and plasma levels were elevated threefold for months after pantethine therapy. Plasma cysteamine concentrations after pantethine were similar to those reported after equivalent doses of cysteamine. However, at best only 80% white blood cell cystine depletion occurred. We conclude that pantethine is probably less effective than cysteamine in the treatment of nephropathic cystinosis and should only be considered in cases of cysteamine intolerance. Serum cholesterol was decreased an average of 14%, which supports the potential clinical significance of pantethine as a hypolipemic agent. Rapid in vivo hydrolysis of pantethine suggests that pantothenate or cysteamine may be the effectors of its hypolipemic action.

Topics: Adolescent; Amidohydrolases; Animals; Child; Cysteamine; Cystine; Cystinosis; Diarrhea; Female; GPI-Linked Proteins; Humans; Intestinal Absorption; Intestinal Mucosa; Kinetics; Leukocytes; Male; Pantetheine; Rats; Rats, Inbred Strains; Sulfhydryl Compounds

Topics: Cysteamine; Cystinosis; Humans; Orphan Drug Production; Pantetheine

Renal cell cultures were initiated using fresh autopsy material from two individuals with cystinosis, ages 5 and 8 yr. Cells obtained from collagenase treated autopsy material were grown in a selective kidney medium containing Coon's modified F12, 2.5% fetal bovine serum, transferrin, insulin, selenium, hydrocortisone, PGE1, and fibronectin. These cells had an epithelial appearance, formed domes, and were periodic acid-Schiff positive. Both tight junctions and microvilli were seen by electron microscopy. Fibroblasts had a cloning efficiency of zero in the selective medium and grew poorly compared to their growth in Coon's F12 with 10% fetal bovine serum. The lysosomal cystine content of the renal cells was greatly elevated and comparable to that of fibroblasts from cystinotic patients. Renal cell lysosomal cystine levels were only partially reduced by exposure to either pantethine or the aminothiol, cysteamine. However, exposure to either compound effectively depleted cystinotic cultured fibroblasts of their lysosomal cystine. Study of cultured renal material may have practical significance in pharmacologic considerations.

Topics: Autopsy; Cells, Cultured; Child, Preschool; Cysteamine; Cystine; Cystinosis; Fibroblasts; Humans; Kidney; Male; Pantetheine

Children suffering from cystinosis, a genetic disease characterized by high levels of lysosomal cystine, are currently being treated with cysteamine to lower the cystine levels in their cells. In fibroblasts from these patients, cysteamine and its disulfide, cystamine, are equally effective in lowering cystine levels. We recently reported that pantethine, a dietary precursor of coenzyme A, depletes cystine from cultured, cystinotic fibroblasts as effectively as cystamine. To determine the mechanism of action of pantethine, and of cystamine, we have compared the fate of [35S]cystine-derived metabolites in the presence and absence of these agents. The results indicate that the ability of pantethine to deplete cystine resides in its being a metabolic precursor of cysteamine. Furthermore, both pantethine and cystamine act by generating the mixed disulfide of cysteamine and cysteine in the lysosomes, which is then rapidly excreted from the cells. The fall in intracellular [35S]cystine caused by these agents was not accompanied by a comparable increase in any intracellular metabolite; rather, it could be accounted for by the appearance of mixed disulfide in the medium. There was no accumulation of mixed disulfide in the cells. Radioactivity in cytoplasmic glutathione was, however, increased by cystamine or pantethine. Thus, cysteamine (formed intracellularly in these experiments) undergoes thiol-disulfide exchange with cystine in the lysosomes, producing cysteamine-cysteine mixed disulfide and free cysteine, which enter the cytoplasm. The free cysteine is available to several pathways, including oxidation to the disulfide or the mixed disulfide, and synthesis of glutathione. The mixed disulfide is excreted from the cell, which ultimately depletes the cell of its excess cystine.

Topics: Cells, Cultured; Child; Cystamine; Cystine; Cystinosis; Fibroblasts; Humans; Kinetics; Pantetheine; Skin; Sulfhydryl Compounds

Topics: Cells, Cultured; Cystamine; Cystine; Cystinosis; Dose-Response Relationship, Drug; Fibroblasts; Humans; Pantetheine; Sulfhydryl Compounds

Cysteamine is the most effective agent known for the reduction of the elevated cystine content of cells from patients with cystinosis. A defect in endogenous cysteamine generation could account for many of the metabolic features of this disorder. To test this hypothesis, we have developed improved methods for measuring pantetheinase (cysteamine-generating) activity and intracellular cysteamine levels and used these methods to measure such parameters in cystinotic and normal leukocytes and cultured skin fibroblasts. Pantetheinase activity as defined in the test was similar in extracts of cystinotic and normal cells [leucocytes, normal, 78 +/- 15 (S.E.), cystinotic, 56+/- 6.4; fibroblasts, normal, 9.4 +/- 1.5; cystinotic, 7.7 +/- 1.7]. Cysteamine levels were normal in leukocytes from cystinotics receiving no cysteamine or doses of oral cysteamine too low to reduce leukocyte cystine content. The results indicate that the cause of cystinosis is unlikely to be related to a failure to generate of sustain normal intracellular cysteamine levels.

Topics: Amidohydrolases; Cysteamine; Cystinosis; Fibroblasts; GPI-Linked Proteins; Humans; Leukocytes; Mercaptoethylamines; Pantetheine